Geomorfometria da Bacia Hidrográfica do Rio Côa

Relatório de projecto no âmbito de Bolsa Universidade de Lisboa/Fundação Amadeu Dias (2008/2009)Universidade de Lisboa, Instituto de Geografia e Ordenamento do Território (IGOT)Trabalho integrado no projecto “Territórios de Foz Côa”, componente do “Projecto Museológico do Vale do Côa” (Universidade de Lisboa)A bacia hidrográfica do rio Côa situa-se quase integralmente na Meseta Norte, no NE da Beira. É uma bacia com 2520 km2, predominantemente granítica (73%) e metassedimentar (24%), cujas superfícies aplanadas foram rejuvenescidas pela morfogénese fluvial quaternária, em resposta ao levantamento epirogénico dos terrenos. São objectivos deste trabalho: definir as altitudes em que os planaltos dominantemente se situam (parte I); estudar os factores condicionantes do estádio evolutivo da hipsometria adimensional (integral hipsométrica) e dos perfis longitudinais dos talvegues principais de 25 sub-bacias, e a sua distribuição espacial (parte II); e analisar a influência das condições litológicas na morfometria do terreno (rugosidade topográfica) e na rede de drenagem (densidade de drenagem e densidade hídrica) (parte III). Utilizam-se técnicas automáticas e semi-automáticas, dominantemente análise espacial e modelação espacial em ambiente SIG aplicada à informação altimétrica digital SRTM 3 segundos de arco. Identificou-se um gradiente geomorfométrico S-N, sentido no qual a rugosidade topográfica aumenta e a altitude média diminui. O gradiente da rugosidade topográfica deve-se: (i) à variação espacial do potencial morfogenético dos cursos de água (aumenta para norte); (ii) provavelmente, ao estádio de evolução da propagação N-S dos “impulsos morfogenéticos” desencadeados pela descida do nível de base do rio Côa; (iii) à complexidade morfotectónica do sector NW da bacia, que é atravessado pelo “morfologicamente expressivo” sistema de falhas Bragança-Manteigas. A sobreelevação dos terrenos a SW, associada ao levantamento da Serra da Estrela, e a subsidência dos terrenos a norte, relacionada com o balançamento da Meseta para NW, explica parte importante do gradiente altimétrico. Os planaltos, obedecendo àquele gradiente altimétrico, situam-se em dois intervalos altimétricos principais: a montante do alinhamento de relevos da Marofa localizam-se principalmente no intervalo 710-830m; e a jusante, no intervalo 460-510m. O alinhamento quartzítico ordovícico parece ter tido um papel activo na génese destas características. A influência da litologia na rugosidade é reduzida, relativamente à morfogénese fluvial. Os terrenos graníticos são menos rugosos que os terrenos metassedimentares. A maior densidade de vales das áreas metassedimentares é a causa da sua maior densidade de vales. A rede de drenagem é mais densa nos terrenos graníticos devido essencialmente a maior número de linhas de água de ordem reduzida. Na bacia do Côa, o estádio evolutivo da hipsometria adimensional das sub-bacias é determinado principalmente pelo estádio evolutivo (integral) dos PL dos cursos de água principais (mais longos) que as drenam, o que tem de se entendido à luz da reduzida variabilidade altimétrica do terreno da bacia do Côa. A diversidade espacial da magnitude da descida relativa do nível de base e da erosividade dos cursos de água será a causa principal da inexistência de uma relação linear entre o encaixe fluvial e a integral hipsométrica. A interacção entre a variação espacial da taxa e/ou duração do levantamento tectónico, da capacidade de ajuste da rede hidrográfica, da influência das rupturas de declive regressivas (desequilíbrio do PL relativamente ao nível de base) na morfologia dos perfis longitudinais, e o condicionamento da litologia em vários aspectos (e.g., na erodibilidade do terreno e na génese de rupturas de declive de equilíbrio), são os factores mais importantes para explicar a variação espacial da morfometria dos perfis longitudinais. Em igualdade dos restantes factores, a relação entre o potencial morfogenético (capacidade de ajuste) de determinada bacia e da bacia para a qual drena o curso de água principal daquela é o factor principal para perceber a variação espacial do estádio evolutivo do perfil longitudinal.Universidade de Lisboa; Fundação Amadeu Dia

Longitudinal subglacial bedform semi-automated mapping and measurement

This thesis addresses methodological issues in the morphometric inventorying of relict drumlins and mega-scale glacial lineations (longitudinal subglacial bedforms, LSBs) which pose limits to a robust description of LSB morphometry and thus to testing hypotheses of LSB genesis, with implications for postdicting past, and predicting future, ice sheet behavior. Focus is on a) the adequacy of previously used morphometric measurement methods (MMM) (GIS) and b) the development of LSB semi-automated mapping (SAM) methods. Dimensions derived from an ellipse fitted to the LSB footprint based on Euler’s approximation are inaccurate and both these and orientation based on the longest straight line enclosed by the footprint are imprecise. A newly tested MMM based on the standard deviational ellipse performs best. A new SAM method outperforms previous methods. It is based on the analysis of normalized local relief closed contours and on a supervised ruleset encapsulating expert knowledge, published morphometric data and study area LSB morphometry

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

A major bottleneck in the successful development of central nervous system (CNS) drugs is the discovery and design of molecules that can cross the blood-brain barrier (BBB). Nano-delivery strategies are a promising approach that take advantage of natural portals of entry into the brain such as monoclonal antibodies (mAbs) targeting endogenous BBB receptors. However, the main selected mAbs rely on targeting broadly expressed receptors, such as the transferrin and insulin receptors, and in selection processes that do not fully mimic the native receptor conformation, leading to mistargeting and a low fraction of the administered dose effectively reaching the brain. Thus, there is an urgent need to identify new BBB receptors and explore novel antibody selection approaches that can allow a more selective delivery into the brain. Considering that in vitro models fail to completely mimic brain structure complexity, we explored an in vivo cell immunization approach to construct a rabbit derived single-domain antibody (sdAb) library towards BBB endothelial cell receptors. The sdAb antibody library was used in an in vivo phage display screening as a functional selection of novel BBB targeting antibodies. Following three rounds of selections, next generation sequencing analysis, in vitro brain endothelial barrier (BEB) model screenings and in vivo biodistribution studies, five potential sdAbs were identified, three of which reaching >0.6% ID/g in the brain. To validate the brain drug delivery proof-of-concept, the most promising sdAb, namely RG3, was conjugated at the surface of liposomes encapsulated with a model drug, the pan-histone deacetylase inhibitor panobinostat (PAN). The translocation efficiency and activity of the conjugate liposome was determined in a dual functional in vitro BEB-glioblastoma model. The RG3 conjugated PAN liposomes enabled an efficient BEB translocation and presented a potent antitumoral activity against LN229 glioblastoma cells without influencing BEB integrity. In conclusion, our in vivo screening approach allowed the selection of highly specific nano-antibody scaffolds with promising properties for brain targeting and drug delivery

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved